Nitro-trifluoromethylbenzamides



United States Patent 3,518,305 NITRO-TRIFLUOROMETHYLBENZAMIDES Dean E. Welch, 800 Beck St., and Robert R. Baron, 3009 Clark St., both of Charles City, Iowa 50616 No Drawing. Filed Aug. 14, 1967, Ser. No. 660,179 Int. Cl. C07c 103/22 US. Cl. 260558 9 Claims ABSTRACT OF THE DISCLOSURE A new series of nitro-trifiuoromethylbenzamides and feed compositions containing the same to be used for the prevention and control of coccidiosis in animals.

This invention relates to the veterinary arts and more particularly to novel chemical compounds, compositions containing and methods of applying the same in the treatment and control of coccidiosis.

Coccidiosis is a communicable gastro-intestinal disorder and occurs in many animal species. It is especially prevalent in poultry and may be produced by a variety of protozoan parasites. The more important species of the pathogenic series are: Eimeria tenella, Eimeria necatrix, Eimeria acervulimz, and Eim'eria brunetti. The pathological conditions created by this disease are of a diverse nature and may range from lingering syndromes of morbidity and emaciation to a heavy toll of fatalities depending on the virulence of the respective parasite and the impact of the infection. Coccidiosis, therefore, causes serious financial losses to the poultry industry in that the market value of the aifiicted birds is considerably diminished and the flock population quite frequently decimated. Also, the epizootic often strikes in form of multiple infections which progress concomitantly and aggravate the deterioration of a flock beyond redemption. Early prophylactic control of the disease is therefore imperative and the remedies desired for this purpose should not only have a high potency at subtoxic levels and low concentrations, but also develop a broad spectrum of eflicacy against the most common species of coccidia.

We have discovered a new series of organic compounds which are possessed of such valuable therapeutic properties both in respect of their high potency and their wide range of coccidiostatic action. Our new compounds may be generically described as derivatives of nitro-trifiuoromethylbenzamides of the following configuration OzN CF wherein X may be oxygen or sulfur, R and R may be either identical or different and stand for hydrogen, alkyl, alkenyl, halogen-substituted alkyl, halogen-substituted alkenyl, lower alkoxy-substituted alkyl, and lower alkoxy-substituted alkenyl groups. Preferred structures within the general purview of our invention are compounds in which the trifluoromethyland nitro-substituents in the benzene ring are paired in the 3,5-, the 2,4- and the 3,4-positions as represented by the formulae:

3,518,305 Patented June 30, 1970 The following compounds are listed as representative members of the series of nitro-trifluoromethylbenzamides within the scope of our invention:

3-trifluoromethyl-5-nitrobenzamide 3-trifiuoromethyl-N-Inethyl-5 -nitrobenzamide 3trifiuoromethyl-N,N-dimethyl-5-nitrobenzamide 3-trifluoromethyl-N-ethyl-5 -nitrobenzamide 3-trifluoromethyl-N,N-diethyl-S-nitrobenzamide 3-trifiuorornethyl-N-allyl-5-nitrobenzamide 3-trifiuoromethyl-N- 2-chloroethyl -5-nitrobenzamide 3 -trifluoromethyl-N Z-methoxyethyl) -5-nitrobenzamide 3 -trifluoromethyl-5-nitro-thiobenzamide 3-trifiuoromethyl-4-nitrobenzamide 2-trifluoromethyl-4-nitrobenzamide The 3-trifluoromethyl-S-nitrobenzamide and its N-substituted derivatives may be conveniently prepared by halogenation of 3-trifiuoromethyl-5-nitrobenzoic acid and subsequent reaction with NH OH or the corresponding amine. The starting material may be obtained in accordance with the method described by Hauptschein et al. in J. Am. Chem. Soc. 76, 1051 (1954).

Members of the 2 trifluoromethyl-4-nitrobenzamide series are similarly produced from the precursory benzoic acid the synthesis of which is described in US. Pat. No. 3,052,603.

The 3-trifiuoromethyl-4-nitrobenzamide is derived from the corresponding nitrile by reaction with hydrogen peroxide in an alkaline medium. The nitrile is formed according to the method of Caldwell et al. outlined in J. Am. Chem. Soc. 73, 5125 (1951).

In order to produce the thiobenzamides of the abovegiven configuration the corresponding benzamides are reacted with phosphorus pentasulfide whereby the oxygen in the benzamide group is exchanged for a sulfur atom.

The following examples will illustrate in greater detail the synthesis of a number of typical representatives of our new anticoccidial compounds.

EXAMPLE 1 3 -trifiuorometh yl-5nitrobenzamide 50 grams (0.211 mole) of 3-trifiuoromethyl-5-nitrobenzoic acid are added to 72 ml. of thionyl chloride and the mixture is heated at reflux for a period of 4 hours. The mass is thereupon cooled and, after the removal in vacuo of unreacted thionyl chloride, quenched in 1 liter of ammonium hydroxide. The resulting precipitate is separated by filtration, washed with water and dried. It accrues in an amount of 37.4 grams or 76% of the theory. The material is a solid, white and odorless substance with a melting point of 139-140 C. Upon analysis it was found to contain:

Carbon 41.07 (calculated value 41.03)

Hydrogen 2.16 (calculated value 2.15)

Nitrogen 11.94 (calculated value 11.97)

Fluorine 24.04 (calculated value 24.34)

EXAMPLE 2 3-trifiuoromethyl-N-methyl-5-nitrobenzamide 38 grams (0.61 mole) of 3-trifiuoromethyl-5-nitrobenzoic acid are added to 150 ml. of freshly distilled thionyl chloride and the mixture is heated at reflux for a period of 4 hours. The excess of thionyl chloride is removed in vacuo and the viscid residue is added to a mixture of 30.4 ml. (0.35 mole) of 40% monomethylamine, 15 grams of sodium bicarbonate and ml. of water. The resulting suspension is heated for one hour at 90 C., chilled and filtered. The residue is washed with water and recrystallized from aqueous denatured alcohol. The compound is collected in an amount of 31 grams or 77.5%

of the theory. It is a solid white material with a melting point of 107-108 C.

EXAMPLE 3 3-trifluoromethyl-N,N-dimethyl-5-nitrobenzamide 3-trifluoromethyl-S-nitrobenzoic acid is reacted with thionyl chloride in the same manner and proportions as in Example 2. After the removal of residual SOCl the viscous mass is added to 45 grams of 30% dimethylamine (0.35 mole) and 15 grams of sodium bicarbonate dissolved in 75 ml. of water. The resulting mixture is heated at 60 C. for one hour, cooled and filtered. The compound accrues as a solid White substance in a yield of 30.7 grams or 73% of the theory. It has a melting point of 5557 C.

EXAMPLE 4 3-trifluoromethyl-N-ethyl-5-nitrobenzamide 3-trifluoromethyl-S-nitrobenzoic acid is chlorinated as in Example 2. After the removal of the residual thionyl chloride the mass is quenched in a mixture of 48 grams of 33% ethylamine (0.35 mole), 15 grams of sodium bicarbonate and 75 ml. of water. It is thereupon heated for one hour at 60-70 C., cooled and filtered. After recrystallization from aqueous denatured alcohol the prodnot is obtained as a solid white material in an amount of 9.5 grams or 22% of the theory. Its melting point is 98-101 C.

EXAMPLE 5 3-trifluoromethyl-N,N-diethyl-S-nitrobenzamide 3-trifluoromethyl-5-nitrobenzoic acid is chlorinated as in Example 2. After the removal of residual thionyl chloride the mass is quenched in a mixture of 25.6 grams (0.35 mole) of diethylamine, grams of sodium bicarbonate and 75 ml. of water at a temperature below 50 C. The mass is then heated for one-half hour at 70 C., cooled and the oily layer is extracted with chloroform. The extract is dried over anhydrous magnesiumsulfate, freed of chloroform in vacuo and the oily residue is distilled. The new substance is a pale yellow liquid with a boiling point of 140-145 C./ 15 mm. It accrued in an amount of 41.7 grams or 89% of the theory.

EXAMPLE 6 3-trifluoromethyl-N-allyl-S-nitrobenzamide 40 grams (0.172 mole) of 3-trifluoromethyl-5-nitrobenzoic acid are treated under reflux with 140 ml. of thionyl chloride for 4 hours. After the removal of excess thionyl chloride in vacuo the mass is quenched in a mixture of 11.4 grams (0.20 mole) of monoallylamine, 60 grams of sodium bicarbonate and 250 ml. of water. The resulting suspension is heated for one-half hour at 50 C., cooled and filtered. The residue is washed with water and dried. The new compound is obtained as a solid white material in an amount of 37.5 grams or 79.5% of theory. It has a melting point of 68-70 C.

EXAMPLE 7 3-trifluoromethyl-N- (2-chloroethyl) -5-nitrobenzamide 31 grams (0.131 mole) of 3-trifiuoromethyl-5-nitrobenzoic acid are refluxed with 150 ml. of thionyl chloride for 4 hours. The excess thionyl chloride is removed in vacuo and the mass is quenched in a mixture of 19.6 grams (0.17 mole) of beta-chloroethylamine hydrochloride, 75 grams of sodium bicarbonate and 250 ml. of water. The resulting suspension is heated for one-half hour at 40 C., cooled and filtered. After washing and drying the substance is recovered as a white solid material in an amount of 31.7 grams or 82% of the theory. It has a melting point of 8790 C.

4 EXAMPLE 8 3-trifiuoromethyl-N- 2-methoxyethyl -5-nitrobenzamide 3-trifluoromethyl-S-nitrobenzoic acid is treated as in Example 6 and after the removal of the residual chlorinating agent, the mass is poured into a mixture of 18.8 grams of Z-methoxyethylamine, 15 grams of sodium bicarbonate and 75 ml. of water. The mixture is heated for one hour at 60 C., cooled and filtered. The precipitate is recrystallized from a mixture of water and ethanol and yields 24.2 grams or 48.5% of the theory of a white solid substance with a melting point of 75.5 to 77.5 C. Upon analysis it was found to contain':

Carbon 45.23 (calculated value 45.21)

Hydrogen 3.85 (calculated value 3.80) Nitrogen 9.55 (calculated value 9.59) Fluorine 19.15 (calculated value 19.50)

EXAMPLE 9 3-trifluoromethyl-S-nitrothiobenzamide 6.9 grams of 3-trifluoromethyl-S-nitrobenzamide as prepared by the method in Example 1 are heated to C. in 50 ml. of xylene and mixed with 3.3 grams of phosphorus pentasulfide. The mixture is kept at a temperature of 110 C. for 30 minutes, filtered hot and the insoluble portion is washed with xylene and the filtrates are combined. The resulting solution is purified with charcoal and cooled. A precipitate is collected and air-dried yielding 3.7 grams of a yellow solid with a melting point of 99- 116 C. The filtrate is concentrated in vacuo to a solid residue. A second crop of 0.8 gram with a melting point of 108-118 C. is obtained by recrystallization of the residue from aqueous denatured alcohol, bringing the yield to a total of 4.5 grams or 60% of the theory. Several recrystallizations give a melting point of 131.5- 132.5 C. Upon analysis the compound was found to contain:

Carbon 38.70 (calculated value 38.40)

Hydrogen 2.14 (calculated value 2.01)

Nitrogen 11.37 (calculated value 11.20)

Fluorine 22.89 (calculated value 22.78)

Sulfur 12.74 (calculated value 12.81)

EXAMPLE 10 3-trifluoromethyl-4-nitrobenzamide 4 grams of 3-trifluoromethyl-4-nitrobenzonitrile are mixed with 15 ml. of 190 proof ethanol and 1 ml. of 6 N NaOH. This mixture is treated dropwise with 10 ml. of 30% hydrogen peroxide at a temperature of 35-50 C. and then stirred for 2 hours at 50 C. A solid precipitate with release of oxygen is formed. The mass is diluted with 25 ml. of water, cooled and filtered. The filter residue is washed with water and dried. The substance is collected as a white solid in an amount of 3.4 grams or 76.4% of the theory and has a melting point of 136-138 C.

EXAMPLE 11 2-trifluoromethyl-4-nitrobenzamide 39 grams of 2-trifluoromethyl-4-nitrobenzoic acid are treated with ml. of thionyl chloride under reflux for 3 hours. After the removal of the excess SOCI in vacuo the mass is quenched in cold concentrated ammonia under stirring for a short period of time. The product is then filtered and washed with water. It is recrystallized from aqueous denatured alcohol and accrues in tan colored solid crystals with a melting point of -192 C. in a yield of 33 grams or 84.4% of the theory.

In accordance with our invention the above-described coccidiostats which are readily acceptable to the animals and at their effective dosage levels do not adversely interfere with their physiological functions are advantageously applied by introducing the same into the animal organism in any form or manner in which they are capable of forming and maintaining an effective blood or tissue level. This can be accomplished by injection or by dispensation of suitable dosage units in capsules or tablets of conventional composition. As a preferred embodiment, however, the compounds are administered to the animals in combination with a solid, inert, non-toxic carrier material in which they are uniformly and homogeneously dispersed. Such inactive vehicles of ingestible nature are any kind of vegetable food material like ground corn, corn meal, dried distillers grain, citrus meal, ordinary grain, mash, scratch, and any other normal or commercial rations. The so medicated feed is placed before the birds for consumption ad libitum. The compounds may also be used as active ingredients in liquid compositions which can be conveniently prepared by means of drinking water in which they are either dissolved or suspended with the help of skim milk, edible oils, syrups or commercial wetting agents and emulsifiers.

The new drugs are principally, though not exclusively, intended for prophylactic purposes to prevent the eruption and spread of a latent infection and as such are to be fed on a continuous schedule. When, for instance, an impending outbreak of coccidiosis in a mature flock is suspected by reason of exposure or a sporadic appearance of the first clinical symptoms of the disease, the remedies are administered to the birds approximately for 2-3 weeks, but treatment may be extended for a longer period if the infection is of more serious nature.

As previously set forth, our new chemotherapeutic agents have been found of principal use in the control of 4 prevalent coccidiogenic parasites which include the bloody cecal species Eimeria tenlla, the bloody intestinal species or Eimeria necatrix, the so-called chronic intestinal species Eimeria acervulina, and the catarrhal intestinal species Eimeria brunetti. Depending on the nature and origin of the infection the minimum dosages for effective control may be as low as 0.00625% or 62.5 parts per million in the feed as for the prevention of E. tenella. In the case of other species or multiple infections the amount may have to be doubled or progressively increased and it has been ascertained that dosages up to 0.1% can be dispensed without untoward reactions. It will likewise be understood that the posological requirements will vary with the potency of the individual members of our new series of compounds as will appear in greater detail from the tables below summarizing the experimental results.

The utility of our new veterinary remedies has been illustrated by testing their prophylactic action against avian coccidiosis of various etiological sources. For each test either broiler-type heavy-breed birds or hybrid Leghorn chicks in groups of 4 were reared in electrically heated brooding batteries, and particular care was taken to protect the animals against extraneous exposure to coccidia and other infective organisms. At 4 to 6 weeks of age the birds were placed in individual cages which had been thoroughly cleaned and disinfected. Feed and water cups were sterilized with steam. The birds were observed for 1 to 2 days for possible sickness. Unhealthy specimens were replaced by wholesome substitutes. During the observation period the chicks became adjusted to their new environment and acquired test-fitness. Each chick was Weighed starting from the day of the experiment. The birds were then moved from one cage to another so as to ensure approximate equality of the mean weights of each test group.

The coccidiosis cultures used in these experiments had been serially propagated over a period of several years. These cultures were started from single oocyst isolates and were grown in coccidia-free birds to ensure their purity. They were periodically subcultured to maintain their virulence. For artificial infection a single close of about 100,000 sporulated oocysts of E. tenella, E. necatrix, and 200,000 oocysts of E. brunetti were given to each chick, while the infective amount of E. acervulina was approximately 5,000,000 sporulated oocysts. Inocluation was carried out by depositing a predetermined volume of a calibrated oocyst suspension directly into the crop of each chick. Treatment by medicated rations was initiated 2 or 3 days before infection and extended over a period of 1014 days depending upon the coccidiogenic species involved.

The criteria of anticoccidial efiicacy in these experiments were (1) the percentage ratio of mean weight gains or losses, (2) the fecal score, and (3) the rate of mortality. The readings in each of the three categories were compared with those of infected, but untreated chicks which served as controls.

The percentage ratio of mean weight variations is an index of the degree of morbidity induced by the stress of the infection. The extent of the counteracting effect of the drug reflects its therapeutic value. The readings are taken during the 10 to 14 day period of the coccidial infection when the same causes the maximum inhibition of growth. Assuming, for instance, the mean weight increase of an infected-medicated group is 180 grams, and that of the non-infected and non-medicated birds is 200 gm., the ratio percentage of mean weight gain would be indicating that due to the beneficial action of the drug the subnormal growth occasioned by the infection fell only by 10%. If, by comparison, the mean Weight gain of the infected, but not medicated controls is only 50%, it would show that the medication has checked the stunting effect of the disease to an extent of 40%. As will be seen from the tabulation, the percent ratios of mean weight deviations from the normal growth rate in the infected but untreated controls carry in some cases a minus sign which signifies that the infection has caused outright emaciation.

The fecal score is rated by a companison of the appearance of the droppings between healthy and infected birds. The score is expressed in percentages and computed in the following manner. Beginning on the third or fourth and continuing through the eighth day after experimental inoculation the droppings of each bird are carefully examined and their deviations from the normal appearance are graded in accordance with accepted practice as outlined by R. R. Baron et al. in Poultry Science, vol XLV, No. 2, March 1966, p. 412. A fecal score of 0 indicates normalcy, while a rating of 4 denotes the maximum degree of deviation. The percent fecal score for each infected-medicated group is calculated on the basis of the maximal degree of the infection reached by each bird of the group within a given time. Assuming that in a group of 4 infected-untreated controls each bird shows the maximum score of 4 at the peak of the infection, the total score of the entire group would be 16. If, on the other hand, the four infected-medicated test animals would score a deviation of l+2+2+2, the total score would be 7. The difference between the two totals divided by the maximum rating established for the infected-nonmedicated controls represents the fecal score, thus X 100 or, rounded to the nearest 5%=55% TABLE I Percent Cone ratio of Survival I No. in mean wt. Fee Losses ratio, Compound Organism birds feed gains score 0. percent 4 0.00500 77. 6 95 100 4 0. 01000 91. 8 100 0 100 3-trifluoromctl1yl-5-nitrobenzamlde E. tenella 4 0. 01500 90. 100 0 100 4 0. 02000 100. 3 100 0 100 4 0. 03000 93. 0 100 0 100 4 0. 04000 65. 8 100 0 100 Infected Controls ..do 4 68. 6 45 0 100 4 0. 00625 113. 4 95 0 100 4 0 01250 117. 0 100 0 100 3-trif1uoromethy1-5nitrobenzamlde .do 4 0. 02500 109. 5 100 0 100 4 0. 05000 69. 0 100 0 100 Infected Controls ..do 4 64.8 0 100 4 0. 01000 84. 5 50 1 75 4 0. 01500 109. 3 100 0 100 4 0. 02000 88. 5 100 0 100 3-trifluoromethyl-5-nitrobenzamide E. necatrix 4 0. 02500 94.0 100 0 100 4 0. 03000 87. 1 100 0 100 4 0. 04000 66. 4 100 0 100 4 0. 05000 73. 8 100 0 100 Infected Controls .d0 4 -0. 1 0 2 50 4 0. 00625 74. 6 55 0 100 3-trifluoromethyl-5-nitrobenzamide ..do 4 0. 01250 97. 7 90 0 100 4 0. 02500 106. 6 100 0 100 4 0. 05000 59. 2 100 0 I00 Infected Controls do 4 17. 2 O 3 4 0. 00625 49. 0 0 100 3-triflueromethyl-S-nitrobenzamide E. acervulina. 4 0.01250 48.1 0 100 4 0. 02500 44. 8 0 100 4 0. 05000 36. 4 100 0 100 Infected Controls do 4 43. 3 0 0 100 4 0.00500 41. 6 15 1 4 0.01500 63. 4 45 0 100 4 0. 02000 74.4 65 0 100 3-trifiuoromethyl-5-nitrobenzamlde E. brunetti 4 0. 02500 73. 6 45 0 100 4 0. 03000 82. 7 65 0 I00 4 0. 04000 79. 8 100 0 100 4 0. 05000 52. 0 100 0 100 Infected Controls ..d0 4 3. 8 0 2 50 TABLE II Percent Cone ratio of Survival No. in mean wt. Fee. Losses ratio, Compound Organism birds feed gains score No. percent 4 73. 7 15 1 75 3-trlfluoromethyl-N-methyl-5nitrobenzsnnide E.tenella 4 90. 4 100 0 100 4 104. 0 100 0 100 Infected Controls .d0. 4 49. 6 0 0 100 4 74. 8 45 1 75 3-trifiuoromethyl-N-methyl-5-nitrobenzamide E. necatrz'z 4 102. 7 100 0 100 4 100. 4 100 0 100 Infected Controls do 4 33. 4 0 3 25 3-trifluoromethyl-N-rnethyl-5-nitrobenzarnidc 4 60. 9 100 0 100 Infected Controls 4 14. 6 0 2 50 3-trifluoromethyl-N-methyl-5-nltrobenzamide 4 0. 02500 39. 9 75 0 100 4 0. 05000 37. 9 0 100 Infected Controls do 34. 2 0 0 100 3-trifluorornetliyl-N-methyl-5-nitrobenzamide E brunetti 4 0. 01250 89. 0 45 0 100 4 0. 02500 101. 8 00 0 100 Infected Controls do 4 24. 1 0 1 75 TABLE III Percent Cone ratio of Survival No. in mean wt. Fee. Losses ratio, Compound Organism bn'ds feed gains score No. percent 3trifluorometl1yl-N ,N-dinlethyl-5nitrobenzamide E tenella g 38 g Infected Controls ..do 40. 6 0 0 100 3-trifiuoromethyl-N,N-dimethyl-fi-nitrobenzamide {Z 8 Infected Controls 24. 2 0 2 50 B-trifluorornethyl-N,N-diinetl1y1-5-nitrobenzamide E. neeatrix {4 0.00625 00. 0 40 0 100 4 0. 02500 100. 3 100 0 100 Infected Controls do 5. 6 0 1 75 3-trifiuoronletyhl-N,N-diincthyl-fi-nitrobeuzamide. 82. 0 0 Infected Controls 33. 4 0 0 100 3-trifluoro1net11yl-N,N-d yl-5-uitrobenzamide 75. 2 100 0 100 Infected Controls l4. 6 0 2 50 3-trifluo1'omethyl-N,N-dimcthyl-5-nitrobenzam1de. E. 38 Infected Controls do 41.2 0 1 75 TABLE IV Percent Cone. ratio of Survival No in mean wt. Fec. Losses ratio, Compound Organlsm lorrds feed gains score N 0. percent Y 4 0. 01250 87. 7 80 100 3 tnfiuoiomethyl N ethyl nitrobenzamidc E. tenella. 0 02500 1 m0 0 100 Infected Controls do 49. 6 0 0 100 3-trifluorornethyl-N-ethyl-5-nitrobenzarnide 4 0. 05000 76. 3 100 0 100 Infected Controls 4 24. 2 0 2 5o 3trifluoromethyl-Nethyl-5-nitrobcnzamide 4 0. 01250 99. 7 100 0 100 Infected Controls do 4 33. 4 0 0 100 I I' 4 0. 02500 105. 8 100 0 I00 N-ethyl-5-nitrobenzamide E. neeatrix 4 0. 05000 76. 5 100 0 100 i 1 4 0. 10000 8. 4 100 0 100 Infected Controls do 4 15. 5 2 1 4 0.05000 44. l 0 100 3-trifiuoromethyl-N-ethyl-fi-nitrobenzarmde E. aceryulma. 10000 6 100 0 100 Infected Controls ..do 4 r 34. 2 o 0 100 8-trifiuorom cthyl-N'ethyl-fi-nitrob enz amide 1 E .brunetti. 4 0. 01250 68. 5 30 0 100 Infected Controls do 4 24. 1 0 I 4 0. 02500 101. 2 100 0 100 3-tr1fluoromethyl-N-ethyl-5-nitrobenzamide do 4 0. 05000 01. 8 100 0 100 4 0. 10000 44. 0 100 O 100 Infected Controls do 41. 2 0 1 75 TABLE V Percent .1 Cone. ratio of Survival No. in mean wt. Fec. Losses ratio, Compound birds feed gains score 0. percent 3-trifiuoromethyLN,N-diethyl-5-nitrobcnzamide 4 0. 01250 95. 8 0 100 Infected Controls 4 49.6 0 0 100 4 0. 02500 96. 8 100 0 100 3-trifluoromethyl-N,N-diethyl-fi-nitrobenzamide do 4 0. 05000 77. 1 100 0 100 4 0. 10000 26. 0 100 0 100 Infected Controls do 4 24. 2 0 2 50 B-trifiuoromethyl-N ,N-diethyl5-nitrobenzamide 4 0. 02500 107. 0 100 0 100 Infected Controls 1 5. 6 0 1 75 3-trifiuoromethY1jN.N-diethyl-5-nitrobenzamide. 4 0. 05000 46. 9 0 Infected Controls 0 0 4 0 3 trifluoromethyPN,N-diethyl--5-n1trobenzamide 4 0. 05000 41. 2 55 O 100 Infected Contro e 1 1. 9 f 0 0 100 3-trifiuoromethyl N ,N-diethyl-5-nitrobenzamide 4 0. 05000 55. 7 90 0 100 Infected Controls do 1 3. 1 0 1 75 TAB LE v1 Percent Cone. ratio of Survival No. in mean wt. Fec. Losses ratio, Compound Organism birds feed gains score 0. percent 4 0. 02500 106. 0 55 0 100 3-trifiuoromethyI-N-ally1-5-nitrobenzamide E. tenella 4 0.05000 105.0 100 0 100 4 0.10000 107.2 100 0 100 Infected Controls do 32. 3 0 1 75 o 3-tritluoromethy 1-N-allyl-5-nitrobenzamide E. necat x i g Infected Controls 5 2 50 3-trifluoromethyLN-a1lyl- 0 100 Infected Controls do 1 75 TABLE VII Percent Cone. ratio of Survival No. in mean wt. Fee. Losses ratio, Compound Orgamsm birds feed gains score 0. percent 8-trifluoromcthyl-N(2-chloroethyl)-5-nitrobenzamide. E. tcnella 88:? 3g 8 Infected Controls do 4 5.0 0 3 25 4 114. 5 100 0 100 3-trifiuoromethyl-N (2-chlorocthyl)-5-nitrobenzamide do 4 106. 5 100 0 100 4 44. 7 100 0 100 Infected Controls 4 32. 3 0 1 75 3-trifluorome'thyl-N (2-chloroethyl)-5-n1trobenzamide i 8%: g 38 g Infected Controls (10 4 4 0 0 88 3-trifluoromethyl-N(2-chloroethyl)-5-nit1obcnZamide .00"... .1 2 8 $8 g i Infected Controls do. 4 15.5 15 2 50 -trifiuoromethyl-N(2-cl1loroethyl)-5-nitrobenzamide E. brunetti. 4 66.9 45 0 100 Infected Controls do .1 4 4. 8 0 1 75 TABLE VIII Percent Conc. ratio of Survival No. in mean wt. Fec. Losses ratio, Compound Organism birds feed gains score No percent E-trifiuoromethyl-N (2-methoxyetl1yl)-5-nitrobenzamide E. tenella 4 0.02500 97. 8 75 0 100 Infected Controls do 2 6.6.666 11g. 0 08 g 1213 3-trifluoromethyl-N (2-methoxycthyl)-5-n1trobenZemide- 4 13000 g 1 0 100 Infected Controls do 4 32. 3 3 a 138 3-trif1uoromethy1-N(Z-methoxyethyl)5nitrobenzamide E. necetrix 4 13000 2: 0 3 0 100 Infected Controls do 4 28. 3 0 3 25 TABLE IX Percent Cone. ratio of Survival No. in mean wt. Fee. Losses ratio, Compound Organism birds feed gains score N percent 4 0. 01250 90. 2 70 0 100 3-tr1fluorornethyl-5-n1troth1obenzarn1de E. tenella 0. 02500 9 95 0 100 Infected Controls do 4 5. 0 0 3 4 0. 02500 116. 8 100 0 100 3-trifluoromethyl-5-nitrothiobenzamide do 4 0. 05000 100. 2 100 0 100 4 0. 10000 48.1 100 0 100 Infected Controls ..do 4 32.3 0 1 75 4 0. 02500 118. 9 90 0 100 3-trifluorometllyl-5nitrothiobenzamlde E. necatriz 4 0. 05000 99. 6 90 0 100 4 0. 10000 49. 4 95 0 100 Infected Controls ..d0 4 28. 3 0 3 25 3-triiluoromethyI-S-nitrothiobenzamide t. E. brunetti 4 0. 05000 0 100 Infected Controls "do 4 0 0 100 TABLE X Percent Cone. ratio of Survival No. mean wt. Fee. Losses ratio, Compound Organism birds feed gains score No. percent 3-trifluoromethyl-4-nitr0b0nZ8mide E- tenella g Infected Controls do 1 100 3-trifluoromethyl-4-nitrobenzarnide. E. necatruc 2 50 Infected Controls do 4 0 TABLE XI Percent Cone. ratio of Survival No. in mean wt. Fee. Losses ratio, Compound Organism birds feed gains score N 0. percent 2-trifluor0methyl-4-nitrobenzamide E. tm lla {2 gfggfigfi 32: 3 38 3 Infected Controls do 4 40. 6 0 0 100 4 0. 02500 97. 5 100 0 100 Z-trifluoromethyl-4-nltrobenzamlde do 4 0. 05000 81. 1 100 0 100 4 0. 10000 97. 6 100 0 100 Infected Controls ..d0 4 24 2 0 2 50 2-trifluoromethyl-4-nitr0benzamide E. mam: 3; ,2 8 $8 Infected Controls -.d0 4 33. 4 0 0 100 th .4- t obenzamide do 4 0.05000 90.6 100 O 100 2 mfluomme yl m r 4 0. 10000 101. 8 100 0 100 Infected Controls flow- 4 I. 15. 6 15 2 2rtriflnoromethyl-4-nitrobenzamide E. brunettz 4 0.05000 45 0 100 Infected Controls v.d 4 0 0 100 As will be seen from the foregoing tables, all of the eleven representative test compounds have at least a 2- species effect, while 7 have a 3-species range and 4 cover the full spectrum of the above described primary coccidiogenie factors. Three of the drugs afford an up to 100% protection at the exceedingly low level of 0.00625 while some of their homologues exhibit comparable potency at dosages between 100 and 1000 parts per million. For the proper evaluation of the experimental results it should be further understood that the values recorded for each of the three criteria of efficacy are in most instances not to be read in isolation from but in conjunction with each other in order to assign them their true significance. Thus, for example, in a sublethal infection the difference in survival ratios between test birds and controls may be 0. This, however, does not detract from the efficacy of the compound when due consideration is given to the fecal score together with the percent ratio of the mean weight gains which may be a multiple of those of the infected controls. On the other hand, in a given case the fecal score may not be higher than 40%, but the ratio of survival is 75% above the controls and the ratio of weight gains is seventeen fold that of the infected but untreated animals. It. will, therefore, be seen that for correct interpretation the tabulated data must be related to and coordinated with each other, taking into account the pathological impact and the clinical syndrome of the disease which vary from species to species.

The preparation of the medicated feed compositions is carried out by intimately mixing the active ingredient with an orally ingesti ble carrier material, such as'feed, in the amount of 5 to 95% by weight and introducing a proportionate quantity of this premix into the bulk of a commercial feed ration with thorough stirring and shuffiing until a uniform blend of even distribution at the desired concentration level is obtained. Commercial feed rations of the type employed in our experiments included normal constituents in a mash or scratch supplemented with desirable amounts of vitamins, trace minerals, antibiotics, growth stimulants and preservatives.

To facilitate the handling of the small amounts of chemicals to be incorporated into the ultimate medicated ration the premix can also be prepared by grinding a limited quantity of a non-toxic inert vehicle with an amount from 5 to by weight of the drug. In this case the carrier material may consist of fullers earth, talcum, bentonite, ground oyster shells, limestone and divers clays, or edible feed substances such as soybean meal, wheat middlings and corn meal, and such stock concentrates are specifically made and adapted for use in dilutions with an edible carrier so as to compound the medicated rations at the desired dosage levels with utmost convenience. The availability of such concentrates is therefore highly desirable, if not indispensable, for the feed manufacturer and poultry raiser who ordinarily uses about one pound of the premix or concentrate for each ton of commercial feed to produce the finished medicated ration.

What we claim is:

1. A chemical compound represented by the formula wherein R and R may be identical or different and stand for hydrogen, alkyl of 1-2 carbons, chloroethyl, ally], and alkoxyethyl in which the alkoxy group has 1-4 carbon atoms.

2. 3-trifluoromethyl-5-nitrobenzamide.

3. 3-trifluoromethyl-N-methyl-S-nitrobenzamide.

4. 3-trifluoromethyl-N,N-dimethyl-S-nitrobenzamide. 5. 3-trifluoromethyl-N-ethyl-S-nitrobenzamide.

References Cited UNITED STATES PATENTS 1962 Hauptschein et al. 260-52l OTHER REFERENCES Caldwell et al.: J. Am. Chem. Soc., vol. 73, pp. 5125- 26 (1951).

Smith: Open-Chain Nitrogen Compounds, vol. 1, p. 212 (1965), QD 412 NIS6.

Yagupolskii et al.: I of General Chemistry of USSR, vol. (1965), pp. 976-82.

HENRY R. JILES, Primary Examiner H. I. MOATZ, Assistant Examiner US. Cl. X.R. 

